There is a significant medical need for improved treatment of both melanoma and colorectal cancers, particularly when they are metastatic to liver. There are approximately 54,200 new cases of malignant melanoma diagnosed annually in the United States. See Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun M J, Cancer statistics, CA Cancer J Clin 53, 5-26, 2003.
Slightly more than 6% of the new cases of malignant melanoma diagnosed annually in the United States are primary ocular melanoma. See Chang A E, Karnell L H, Menck H R., The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade, Cancer 83, 1664-1678, 1998.
An estimated 153,760 new cases of colorectal cancer (CRC) were diagnosed in the United States and there were 52,180 deaths from this disease in 2007 (American Cancer Society, Cancer Facts and Figures, 2007).
Unresectable hepatic metastases from solid organ malignancies represent a significant therapeutic challenge in oncology. See Pingpank J F, Libutti S K, Chang R, Wood B J, Neeman Z, Karn A W, Figg W D, Zhai S, Beresneva T, Seidel G D, Alexander H R, Phase I Study of Hepatic Arerial Melphalan Infusion and Hepatic Venous Hemofiltration Using Percutaneously Placed Catheters in Patients with Unsectable Hepatic Malignancies, J Clin Oncol 23, 3465-3474, 2005.
For patients with colorectal adenocarcinoma, ocular melanoma, and neuroendocrine tumors, liver metastases frequently represent the sole or predominant site of disease progression. For these patients, systemic and hepatic arterial chemotherapy results in median survivals ranging from 12 to 24 months. See Rothenberg M C, Oza A M, Bigelow R H et al., Superiority of oxaliplatin and fluourouracilleucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial, J Clin Oncol 21, 2059-2069, 2003. See Kemeny N, Gonen M, Sullivan D, et al., Phase I study of hepatic arterial infusion of floxuridine and dexamethasone with systemic irinotecan for unresectable hepatic metastases from colorectal cancer, J Clin Oncol 19, 2687-2695, 2001.
For patients with metastatic ocular melanoma who recur, 70% to 90% will develop disease confined to the liver that is multifocal and not amenable to surgical resection. See Egan K M, Seddon J M, Glynn R J, Epidemiologic aspects of uveal melanoma, Surv Ophthalmol 32, 239-251, 1988.
Systemic and regional chemotherapy or ablative techniques do not seem to meaningfully impact the natural history of the disease. See Gragoudas E S, Egan K M, Seddon J M., Survival of patients with metastases from uveal melanoma, Ophthalmology 98, 383-390, 1991. See Kath R, Hayungs J, Bornfeld N, et al., Prognosis and treatment of disseminated uveal melanoma, Cancer 72, 2219-2223, 1993.
Intra-arterial chemotherapy has recently been shown to result in remarkable clinical outcomes because of higher intratumoral concentrations of oncostatics despite minimal adverse effects as compared with those administered systemically. See Eckman W W, Patlak C S, Fenstermacher J D, A critical evaluation of the principles governing the advantages of intra-arterial infusions, J Pharmacokinetic Biopharm 2, 257-85, 1974. See Vermorken J B., The role of chemotherapy in squamous cell carcinoma of the uterine cervix: a review, Int J Gynecol Cancer 3, 129-142, 1993. See Kusunoki N, Ku Y, Tominaga M, Iwasaki T, Fukumoto T, Muramatsu S, Sugimoto T, Tsuchida S, Takamatsu M, Suzuki Y, Kuroda Y., Effect of sodium thiosulfate on cisplatin removal with complete hepatic venous isolation and extracorporeal charcoal hemoperfusion: a pharmacokinetic evaluation, Ann Surg Oncol 8, 449-57, 2001. See Tominaga M, Ku Y, Iwasaki T, Suzuki Y, Kuroda Y, Saitoh Y., Pharmacological evaluation of portal venous isolation and charcoal Hemoperfusion for high-dose intra-arterial chemotherapy of the pancreas, Br J Sur 84, 1072-6, 1997. See Jones A and Alexander, Jr. H., Development of isolated Hepatic Perfusion for patients who have unresectable hepatic malignancies, Surg Oncol Clin N Am 17, 857-876, 2008.
A higher antitumor effect has generally been accepted to be correlated with higher dose intensity, but is associated with severe toxicity. See Maruo T, Motoyama S, Hamana S, Yoshida S, Ohara N, Yamasaki M, Ku Y., Percutaneous pelvic perfusion with extracorporeal chemofiltration for advanced uterine cervical carcinoma, Surg Oncol Clin N Am 17, 843-56, 2008.
The liver has a unique anatomy that provides an opportunity to deliver regional therapy. Established hepatic metastases derive the majority of their blood supply from the hepatic artery, and hepatic arterial infusion of agents with high hepatic clearance during the “first pass” through the hepatic parenchyma allows infusion of high doses of chemotherapy to the diseased organ. See Sigurdson E R, Ridge J A, Daly J M, Fluorodeoxyuridine uptake by human colorectal hepatic metastases after hepatic artery infusion, Surgery, 1986; 100:285-291.
Percutaneous Hepatic Perfusion (PHP), allows physicians to deliver significantly higher doses of anti-cancer drugs to the site of disease without exposing the patient's entire body to those same potent levels of drug. PHP uses a double balloon catheter positioned within the inferior vena cava (IVC) to isolate hepatic venous outflow and divert the blood through an extracorporeal filtration system. Chemotherapy infused through a catheter positioned in the hepatic artery is filtered after the blood exits the liver, so that systemic exposure is limited. The main component of the system is a 16-F, polyethylene double balloon catheter with one large lumen and three accessory lumina. The two low-pressure occlusion balloons are inflated independently. The cephalic balloon blocks the IVC above the hepatic veins, while the caudal balloon obstructs the IVC below the hepatic veins, allowing complete isolation of hepatic venous outflow. The span between the two occlusion balloons consists of a fenestrated segment that feeds into the large central lumen, which exits the catheter from the proximal end. The additional lumen enters the catheter at a point inferior to the caudal balloon and allows some blood flow from the infrarenal IVC to the right atrium. During the procedure, a high dose of a chemotherapeutic agent is infused through a catheter in the hepatic artery. The chemotherapy perfuses the liver and exits the organ through the hepatic veins. Hepatic venous effluent is collected using the double balloon catheter and chemotherapeutic-dosed blood from the central lumen is pumped through an extracorporeal circuit consisting of a centrifugal pump and two activated-carbon filter cartridges arranged in parallel. The filtered blood is returned to systemic circulation via a venous return sheath inserted into the internal jugular vein. Treatments are administered with patients under local or general anesthesia and heparin is administered during the procedure to maintain an ACT of 300 seconds.
The advantages of the PHP approach are that treatment can be delivered without a major operative procedure and that filtration of the hepatic venous effluent can reduce system exposure of cytotoxic chemotherapy by 80% to 90% compared with hepatic artery infusion alone. In clinical trials, 33 patients underwent a total of 77 treatments with dose escalation of doxorubicin from 50 to 120 mg/m2. The systemic exposure of doxorubicin was substantially reduced using hepatic venous hemofiltration. However, because antitumor efficacy was not well established, the technique did not gain widespread application. See Pingpank J F, Libutti S K, Chang R, Wood B J, Neeman Z, Kam A W, Figg W D, Zhai S, Beresneva T, Seidel G D, Alexander H R., Phase I Study of Hepatic Arerial Melphalan Infusion and Hepatic Venous Hemofiltration Using Percutaneously Placed Catheters in Patients with Unsectable Hepatic Malignancies, J Clin Oncol 23, 3465-3474, 2005.
Hemoadsorption, or hemoperfusion (HP) as an extracorporeal technique, was introduced in the early 1960s. See Yatzidis H., A convenient hemoperfusion micro-apparatus over charcoal for the treatment of endogenous and exogenous intoxications: Its use as an effective artificial kidney, Proc Eur Dial Transpl Assoc 1, 83-87, 1964.
Although the initial results were very successful, this HP procedure induced hypotension, hypocalcaemia, hypokalaemia, hypoglycaemia and thrombocytopenia. See Rosenbaum J L. Poisonings. In Giordano C ed., Sorbents and their clinical applications, New York: Academic Press, 451-67, 1980.
The most severe potential complication from use of the HP technique was the release of fine particles from the carbon granules, causing micro-emboli. See Hagstam K E, Larsson L E, Thysell H., Experimental studies on charcoal hemoperfusion in Phenobarbital intoxication and uremia, including histopathological findings, Acta Med Scand 180, 593-610, 1966. See Chang T M., Therapeutic applications of polymeric artificial cells, Nat Rev Drug Discov. 4, 221-35, 2005.
The problem of poor biocompatibility of uncoated adsorbents was resolved by coating adsorbent granules with haemocompatible membranes. See Botella J, Ghezzi P M, Sanz-Moreno C., Adsorption in hemodialysis, Kidney Int Suppl 76, S60-5, 2000. See Hasirci N, Akovali G., Polymer coating for hemoperfusion over activated charcoal, J Biomed Mater Res 20, 963-70, 1986. See el-Kheshen S, Zia H, Badawi A, Needham T E, Luzzi L A., Coating charcoal with polyacrylate-polymethacrylate copolymer for hemoperfusion. III: The effect of the coat thickness on the adsorption capacity of the coated charcoal and its adsorptivity to small and middle size molecules, J Microencapsul 12, 505-14, 1995.
Use of coated adsorbents instead of uncoated ones reduces the efficiency of hemoperfusion. As a result, for many years the use of adsorption was limited to only acute poisoning. See Hanasawa K., Extracorporeal treatment for septic patients: new adsorption technologies and their clinical application, Ther Apher 6, 290-5, 2002. See Legallais C, Gautier A, Dufresne M, Carpentier B, Baudoin R., The place of adsorption and bio-chromatography in extracorporeal liver support systems, J Chromatogr B Analyt Technol Biomed Life Sci. 861, 171-6, 2008. See de Pont A C., Extracorporeal treatment of intoxications, Curr Opin Crit Care 13, 668-73, 2007.
Since the 1990s interest in the use of adsorbents in extracorporeal medical devices has been rising again. See Mikhalovsky S V: Emerging technologies in extracorporeal treatment: focus on adsorption, Perfusion 18, 47-54, 2003.
By their chemical composition, medical adsorbents can be divided into three major groups: i) activated carbon (AC); ii) synthetic and natural organic polymers; and iii) inorganic adsorbents, such as silica and oxides of titanium and zirconium. Activated carbon is the most powerful adsorbent among all the materials, as it has the largest surface area—in excess of 2000 m2/g and pore volume—up to 1.8 cm3/g. See Bansal R C, Donnet J-B, Stoeckli F., Active carbon, New York, N.Y.: Marcel Dekker, 1988.
In addition to its superior adsorption features, activated carbon has a series of other advantages over other adsorbents in this respect. Firstly, activated carbon is a rigid material that does not swell in water or other solvents, unlike polymers, and does not require special pretreatment in such a solvent. It is also easier to maintain stable flow characteristics of a biological fluid through a column packed with carbon granules than through a column with soft polymer granules. Second, activated carbon is chemically inert compared with polymers, as it does not contain any plasticizer, catalyst or monomer that can leak from the material into the bloodstream. See Mikhalovsky S V: Emerging technologies in extracorporeal treatment: focus on adsorption, Perfusion 18, 47-54, 2003.
Use of coated adsorbents instead of uncoated adsorbents dramatically reduces the efficiency of HP, both in terms of adsorption capacity and rate of adsorption. As a result, HP has been limited in use to only acute poisoning with certain low-molecular toxins. See Webb D., Charcoal hemoperfusion in drug intoxication, Br J Hosp Med 49, 493-96. 1993.
As many small molecules are protein bound in the blood, they cannot cross the membrane coating. Hence, HP over coated adsorbents would be efficient in removing only protein-free solutes of low molecular mass.
PHP currently utilizes two single-use hemoperfusion cartridges. The filters are arranged in parallel, through which hepatic venous blood passes to remove the chemotherapeutic agent before entering the venous return circuit. Blood flows range from 400 mL/min to 1.2 L/min (combined flows for the two filters in parallel). The filters are packed with a bed of carbon, either in granular or spherical form, which carbon is coated with an agent to improve biocompatibility. Uncoated charcoal would cause significant damage to the blood, including lysis of red blood cells and clotting activation. Uncoated charcoal also tends to be physically unstable, resulting in fine particulates that may enter the blood and pose a safety concern.
Delcath was forced to change filters during the clinical trials when Asahi removed their Hemosorba device from the market. There is only one commercially available activated carbon blood filter available in North America. Gambro markets the Adsorba C filter which utilizes a cylindrical carbon coated with a cellulose matrix. This filter fails to provide high first pass removal of traditional chemotherapeutic agents and is therefore unsuitable for use within the PHP procedure. Delcath is currently using a filter manufactured by Clark Research & Development. The Clark Biocompatible hemoperfusion cartridge was voluntarily removed from commercial distribution, but continues to be used in clinical trials by Delcath under an agreement with the FDA. The Clark filter uses a granular carbon, with a mean grain size in excess of 0.6 mm, which results in the release of fine carbon particles into the blood and lack blood biocompatibility.
Platinum-based drugs are among the most active anticancer agents and have been widely used in the treatment of a variety of human tumors. See Raymond E, Faivre S, Chaney S, Woynarowski J, and Cvitkovic E., Cellular and Molecular Pharmacology of Oxaliplatin, Mol Cancer Ther 1, 227-235, 2002.
Over the last 30 years, a large number of platinum analogues has been synthesized to enlarge the spectrum of activity, overcome cellular resistance, and/or reduce the toxicity of both first (e.g., cisplatin) and second generation (e.g., carboplatin) platinum drugs. See Cvitkovic E., A historical perspective on oxaliplatin: rethinking the role of platinum compounds and learning from near misses, Semin Oncol 25, 1-3, 1998. See Raymond E, Chaney S G, Taamma A, and Cvitkovic E., Oxaliplatin: a review of preclinical and clinical studies, Ann Oncol 9, 1053-1071, 1998. See Raymond E, Faivre S, Woynarowski J M, and Chaney S G., Oxaliplatin: mechanism of action and antineoplastic activity, Semin Oncol 25, 4-12, 1998. See Soulie P, Raymond E, Brienza S, and Cvitkovic E., Oxaliplatin: the first DACH platinum in clinical practice, Bull Cancer 84, 665-673, 1997. See Cvitkovic E., Ongoing and unsaid on oxaliplatin: the hope, Br J Cancer 77 (Suppl. 4), 8-11, 1998.
Oxaliplatin, a diaminocyclohexane-containing platinum, has a spectrum of activity and mechanisms of action and resistance that appear to be different from those of other platinum-containing compounds, notably cisplatin. Oxaliplatin has a cytotoxic effect in a broad range of cell lines, including colon, ovarian, and lung cancer, with IC50 values ranging from 0.5 to 240 μM in colon, 0.12 to 19.8 μM in ovarian, and 2.6 to 6.1 μM in lung. See Llory J F, Soulie P, Cvitkovic E, and Misset J L., Feasibility of high-dose platinum delivery with combined carboplatin and oxaliplatin, J Natl Cancer Inst (Bethesda), 86, 1098-1099, 1994. See Soulie P, Bensmaine A, Garrino C, Chollet P, Brain E, Fereres M, Jasmin C, Musset M, Misset J L, and Cvitkovic E., Oxaliplatin/cisplatin (L-OHP/CDDP) combination in heavily pretreated ovarian cancer, Eur J Cancer 33, 1400-1406, 1997. See Rixe O, Ortuzar W, Alvarez M, Parker R, Reed E, Paull K, and Fojo T., Oxaliplatin, tetraplatin, cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute's Anticancer Drug Screen panel, Biochem Pharmacol 52, 1855-1865, 1996. See Pendyala L, Kidani Y, Perez R, Wilkes J, Bernacki R J, and Creaven P J., Cytotoxicity, cellular accumulation and DNA binding of oxaliplatin isomers, Cancer Lett 97, 177-184, 1995. See Pendyala L and Creaven P J., In vitro cytotoxicity, protein binding, red blood cell partitioning, and biotransformation of oxaliplatin, Cancer Res 53, 5970-5976, 1993. See Holmes J, Stanko J, Varchenko M, Ding H, Madden V J, Bagnell C R, Wyrick S D, and Chaney S G., Comparative neurotoxicity of oxaliplatin, cisplatin, and ormaplatin in a Wistar rat model, J Toxicol Sci 46, 342-351, 1998. See Raymond E, Lawrence R, Izbicka E, Faivre S and Von Hoff D D., Activity of oxaliplatin against human tumor colony-forming units, Clin Cancer Res 4, 1021-1029, 1998.
In in vivo studies, oxaliplatin is active against breast, colon, and gastric cancer; renal cell carcinoma; and sarcoma. See Pendyala L and Creaven P J., In vitro cytotoxicity, protein binding, red blood cell partitioning, and biotransformation of oxaliplatin, Cancer Res 53, 5970-5976, 1993.
In addition, oxaliplatin has been tested in vitro and in vivo against cisplatin-resistant cell lines and tumor models, including human ovarian, lung, cervix, colon, and leukemia cell lines. The filters used are not specific in their removal of aromatic compounds within a broad molecular weight range, but the available validated method of measuring platinum by atomic absorption permits this study to validate the filter removal and blood biocompatibility for oxaliplatin and perhaps other chemotherapeutic agents to be tested.